Anti-ulcer urea derivatives

ABSTRACT

Urea derivatives of the following formula, ##STR1## wherein R 1  indicates a piperidino group or pyrrolidino group which may be substituted with hydroxy group or lower alkyl group having 1 to 3 carbon atoms; A indicates an ethylene group, propylene group, butylene group or butenylene group; R 2  indicates a straight or branched alkyl group having 1 to 20 carbon atoms, cycloalkyl group having 3 to 6 carbon atoms, benzyl group, or phenyl group which may have 1 to 3 substituents such as lower alkyl group having 1 to 6 carbon atoms, lower alkoxy group having 1 to 3 carbon atoms, halogen atom, trifluoromethyl group, amino group, nitro group or methylenedioxy group; X indicates an oxygen or sulfur atom, the hydrates and pharmaceutically acceptable acid addition salts thereof are useful as antiulcer agents.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel urea derivatives and their medicallyacceptable acid addition salts having a strong gastric antisecretoryactivity together with a strong gastric cytoprotective activity. Thus,the compounds of this invention are useful for the treatment of pepticulcer. This invention also relates to processes for the manufacturethereof.

It has been well-known that gastric acid secretion caused by histamineis mediated by histamine H₂ -receptor, and the blockade of this receptorby its antagonist reduces the gastric acid secretion in animals andhumans (Brimblecombe, R.W., et al., J. Int. Med. Res., 3, 86-92, 1975).Several drugs of this type, such as cimetidine, are commerciallyavailable.

It has also been said that a compound which prevents or cures thegastric lesions induced by a necrotizing agent such as hydrochloric acidor absolute ethanol has gastric cytoprotective activity (Robert, A., etal., Gastroenterology, 77, 433-443. 1979). Gastric cytoprotective effectis achieved independently of the inhibitory action on gastric acidsecretion. In fact, histamine H₂ -receptor antagonists hitherto knowncannot suppress the formation of gastrtic lesions induced by absoluteethanol or 0.6N HCl.

As the similar type of the compounds of the present invention, thecompounds discovered by Allen & Hanburys Limited have been known (Brit.Pat. Publication No. 1,604,674 and 1,604,675). The urea derivativesmentioned in these publications, however, have onlydimethylaminomethylphenoxy group, and no mention is made ofpiperidinomethylphenoxy group. Furthermore, these publications mentionedonly histamine H₂ -receptor antagonistic activity, but no description ismade of gastric cytoprotective activity.

A number of histamine H₂ -receptor antagonists has been developed andthey bring high ulcer-healing rate in clinical therapy. However, it hascome to be drawn as a serious problem that the recurrence and relapse ofpeptic ulcer frequently occur within weeks or a few months afterwithdrawal of administration of histamine H₂ -receptor antagonisthitherto known. Recently, to improve this problem, a concomitant use ofhistamine H₂ -receptor antagonist with gastric cytoprotective agent hascome to be tried in practice.

In addition, it has been well-known that antiulcer drugs having gastriccytoprotective activity are more effective for gastric ulcers than forduodenal ulcers, while histamine H₂ -receptor antagonists are moreeffective for duodenal ulcers than for gastric ulcers.

Therefore, it is expected that a new type of histamine H₂ -receptorantagonist having not only strong gastric antisecretory activity butalso gastric cytoprotective activity can reduce the recurrence andrelapse of peptic ulcer, and also improve the healing rate and healingprocess of peptic ulcer.

To improve the weak points of the known histamine H₂ -receptorantagonists, namely, to prevent the recurrence and relapse of pepticulcer, we have continuously studied for development of the new type ofhistamine H₂ -receptor antagonists. Consequently, we - have succeeded inthe development of histamine H₂ -receptor antagonists having a stronggastric antisecretory activity together with a strong gastriccytoprotective activity.

The compounds of the present invention are novel urea derivativesrepresented by the following formula (I). ##STR2## wherein R₁ indicatesa piperidino group or pyrrolidino group which may be substituted withhydroxy group or lower alkyl group having 1 to 3 carbon atoms; Aindicates an ethylene group, propylene group, butylene group orbutenylene group; R₂ indicates a straight or branched alkyl group having1 to 20 carbon atoms, cycloalkyl group having 3 to 6 carbon atoms,benzyl group, or phenyl group which may have 1 to 3 substituents such aslower alkyl group having 1 to 6 carbon atoms, lower alkoxy group having1 to 3 carbon atoms, halogen atom, trifluoromethyl group, amino group,nitro group or methylenedioxy group; X indicates an oxygen or sulfuratom, the hydrates and pharmaceutically acceptable acid addition saltsthereof.

According to the invention, the compounds represented by the generalformula (I) are prepared through various routes as follows.

(1) The compounds represented by the general formula (I) can be preparedby allowing the compounds of the general formula (II); ##STR3## (whereinR₁ and R₂ have the same meanings as described above) to react withisocyanate derivatives represented by the general formula (III).

    XCN-R.sub.2                                                (III)

(wherein R₂ and X have the same meanings as described above) Typically,they can be prepared by allowing isocyanate derivatives (III) to reactwith compounds of the general formula (II) in a suitable solvent, forexample, alcohol, benzene, chloroform, dichloromethane, and so on. Thereaction temperature is selected appropriately within a range of roomtemperature to boiling point of the solvents. At this time, the additionof a catalyst, such as triethylamine, is also preferable.

(2) The compounds represented by the general formula (Ia); ##STR4##(wherein X₁ indicates an oxygen atom and R₁, R₂ and A have the samemeanings as described above) can be prepared by allowing the compoundsrepresented by the general formula (IV)

    H.sub.2 N-R.sub.2                                          (IV)

(wherein R₂ has the same meaning as described above) to react withcompounds of the general formula (II) in the presence ofN,N'-carbonyldiimidazole. Typically, they can be prepared by the directreaction of amines represented by the general formula (IV) withimidazolecarbonylamides, which are obtained from amines withN,N'-carbonyldiimidazole. They can be also prepared by the directreaction of amines represented by the general formula (II) withimidazolecarbonyl amides, which are obtained from amines (IV) withN,N'-carbonyldiimidazole. There is no different either case of isolationand non-isolation of imidazolecarbonylamides. The suitable solvent ofthis reaction is organic solvent such as benzene, tetrahydrofuran (THF),chloroform, dichloromethane, and so on. The reaction temperature isselected appropriately within a range of room temperature to boilingpoint of the solvents.

(3) The compounds represented by the general formula (Ia) can beprepared by allowing the compounds of the general formula (II) to reactwith the compounds of the general formula (V);

    Y.sub.1 COOY.sub.2                                         (V)

(wherein Y₁ and Y₂ indicate a leaving group each independently) and thecompounds of the general formula (IV). They can be prepared by thereaction that compounds of a general formula (II) are at first convertedto its urethanes in the presence of the compound of the general formula(V) and the urethanes are reacted with compounds of the general formula(IV). They can be also prepared by the reaction that compounds of thegeneral formula (IV) are at first converted to its urethanes in thepresence of the compound of the general formula (V) and the urethanesare reacted with compounds of the general formula (II). There is nodifferent in either case of isolation and non-isolation of urethanes.The suitable solvent of this reaction is organic solvent such asbenzene, THF, chloroform, dichloromethane, dimethylformamide (DMF), andso on. The reaction temperature is selected appropriately within a rangeof room temperature to boiling point of the solvents. At this time, theaddition of the catalysts such as pyridine, triethylamine, and so on, isalso preferable. In this case, it is desirable that leaving group Y₁ ofthe compound represented by the general formula (V) is halogen atom forexample, chlorine or bromine atom and leaving group Y₂ is lower alkylgroup.

(4) The compounds represented by the general formula (I) can be preparedby allowing phenol derivatives represented by the general formula (VI);##STR5## (wherein R₁ has the same meaning as described above) to reactwith compounds represented by the general formula (VII). ##STR6##(wherein Y₃ indicates a leaving group and R₂, A and X have the samemeanings as described above). The suitable solvent of this reaction isorganic solvent such as methanol, ethanol, propanol, isopropanol,3-methoxypropanol, and so on. The reaction temperature is selectedappropriately within a range of 0 ° C. to boiling point of the solvents.At this time, the addition of the catalysts such as basic catalyst, forexample, sodium, sodium hydroxide, potassium hydroxide, sodiumbicarbonate, sodium carbonate, and so on, is also preferable. In thiscase, it is also desirable that leaving group Y₁ of the compoundrepresented by the general formula (VII) is halogen atom for example,chlorine or bromine atom.

(5) The compounds represented by the general formula (I) can be preparedby allowing the compounds represented by the general formula (VIII)##STR7## (wherein R₁, A and X have the same meanings as described above)to react with the compounds represented by the general formula (IV). Thesuitable solvent of this reaction is organic solvent such as ethanol,benzene, chloroform, dichloromethane, THF, DMF, and so on. The reactiontemperature is selected appropriately within a range of room temperatureto boiling point of the solvents At this time, the addition of thecatalyst, such as triethylamine, and so on, is also preferable.

(6) The compounds represented by the general formula (Ic); ##STR8##(wherein R₃ indicates an aminophenyl group and R₁, A and X have the samemeanings as described above) can be prepared by hydrogenation of thecompounds represented by the general formula (Ib). ##STR9## (wherein R₄indicates a nitrophenyl group and R₁, A and X have the same meanings asdescribed above) This reduction is accomplished by the reaction withmetal such as, for example, iron, tin, and so on, in the presence ofacid, such as, hydrochloric acid, acetic acid, and so on, in thesuitable organic solvent, such as, ethanol, isopropanol, dioxane, and soon. The reaction temperature is selected appropriately within a range ofroom temperature to boiling point of the solvents This reduction is alsoaccomplished by the catalytic hydrogenation using palladium on charcoal,and so on, in the inert solvent such as, ethanol, isopropanol,3-methoxybutanol, dioxane, DMF, and so on. The temperature is selectedappropriately within a range of room temperature to boiling point of thesolvents.

Furthermore, the compounds represented by the formula (I) can beconverted to the medically acceptable acid addition salts by treatmentwith acid as usual manner. The acid may be inorganic acid such as,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, andso on, or organic acid such as, acetic acid, propionic acid, citricacid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaricacid, methanesulfonic acid, and so on.

The following examples will further illustrate the present inventionwithout, however, limiting it thereto.

EXAMPLE 1N-(4-Methoxyphenyl)-N'-[3-(3-piperidinomethylphenoxy)propyl]urea

To the mixture of 3-(3-piperidinomethylphenoxy)propylamine (3.1 g) inethanol (31 ml) was added 4-methoxyphenylisocyanate (1.9 g) dropwiseslowly under cooling on an ice-water bath. The reaction mixture wasstirred at room temperature for 2.5 hours and then concentrated underreduced pressure. The resulting residue was dissolved in dichloromethane(50 ml), washed with diluted hydrochloric acid, saturated aqueous sodiumbicarbonate solution and saturated aqueous sodium chloride solutionsuccessively and dried over anhydrous magnesium sulfate. After removalof the solvent under reduced pressure, the crude product (3.3 g) wasobtained (yield 66.0 %). This crude product was recrystallized fromethanol to give the title compound (2.1 g), mp 111°-112° C.

Analysis (%) for C₂₃ H₃₁ N₃ O₃, Calcd. (Found): C, 69.49 (69.28); H,7.86 (7.86); N, 10.57 (10.54).

EXAMPLE 2-50

The analytical data of the compounds of Example 2-50, synthesized assame manner as the process of Example 1, are summarized in Table 1 (1)to (4).

                                      TABLE 1                                     __________________________________________________________________________                                                         Analysis                                                                            Calcd.             Ex.                                          Molecular                                                                             (%)   Found              No.                                                                              R.sub.1    A           X  R.sub.2    mp (°C.)                                                                    formula C  H  N                  __________________________________________________________________________        ##STR10## CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                 ##STR11## 109-111                                                                            C.sub.22 H.sub.29 N.sub.3                                                     O.sub.2 71.90 71.94                                                                      7.95 8.00                                                                        11.43 11.39        3                                                                                 ##STR12## CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                 ##STR13## 103-105                                                                            C.sub.23 H.sub.31 N.sub.3                                                     O.sub.2 72.41 72.31                                                                      8.19 8.15                                                                        11.01 10.92        4                                                                                 ##STR14## CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                 ##STR15## 114-116                                                                            C.sub.23 H.sub.28 F.sub.3                                                     N.sub.3 O.sub.2                                                                       63.43  63.41                                                                     6.48 6.50                                                                        9.65 9.58          5                                                                                 ##STR16## CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                 ##STR17## oily C.sub.23 H.sub.28 F.sub.3                                                     N.sub.3 O.sub.2                                                                       Mass: 435 (M.sup.+)      6                                                                                 ##STR18## CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                 ##STR19## 131-133                                                                            C.sub.22 H.sub.28 ClN.sub.3                                                   O.sub.2 65.74 65.76                                                                      7.02 6.94                                                                        10.45 10.49        7                                                                                 ##STR20## CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                 ##STR21## 58-61                                                                              C.sub.22 H.sub.28 ClN.sub.3                                                   O.sub.2 Mass: 402 (M.sup.+                                                            )                        8                                                                                 ##STR22## CH.sub.2 CH.sub.2 CH.sub.2                                                                O  CH.sub.2 CH.sub.2 CH.sub.3                                                                99-101                                                                            C.sub.19 H.sub.31 N.sub.3                                                     O.sub.2 68.43 68.40                                                                      9.37 9.38                                                                        12.60 12.61        9                                                                                 ##STR23## CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                 ##STR24## 109-112                                                                            C.sub.23 H.sub.31 N.sub.3                                                     O.sub.2 72.41 72.47                                                                      8.19 8.18                                                                        11.01 10.98        10                                                                                ##STR25## CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                 ##STR26## 92-94                                                                              C.sub.23 H.sub.31 N.sub.3                                                     O.sub.3 69.49 69.61                                                                      7.86 7.87                                                                        10.57 10.54        11                                                                                ##STR27## CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                 ##STR28## 80-83                                                                              C.sub.24 H.sub.33 N.sub.3                                                     O.sub.4 67.42 67.34                                                                      7.78 7.74                                                                        9.83 9.83          12                                                                                ##STR29## CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                 ##STR30## 95-98                                                                              C.sub.24 H.sub.33 N.sub.3                                                     O.sub.4 67.42 67.28                                                                      7.78 7.73                                                                        9.83 9.81          13                                                                                ##STR31## CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                 ##STR32## 114-118                                                                            C.sub.23 H.sub.31 N.sub.3                                                     O.sub.3 .HCl.H.sub.2                                                                  61.12 61.33                                                                      7.58 7.36                                                                        9.30 9.30          14                                                                                ##STR33## CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                 ##STR34## 64-66                                                                              C.sub.22 H.sub.28 N.sub.4                                                     O.sub.4 Mass: 412 (M.sup.+)      15                                                                                ##STR35## CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                 ##STR36## Oily C.sub.22 H.sub.28 N.sub.4                                                     O.sub.4 .1/2 H.sub.2                                                                  62.69 62.89                                                                      6.93 6.81                                                                        13.29 13.31        16                                                                                ##STR37## CH.sub.2 CH.sub.2 CH.sub.2                                                                O  CH.sub.2 CH.sub.3                                                                          80-81.5                                                                          C.sub.18 H.sub.29 N.sub.3                                                     O.sub.2 67.68 67.61                                                                      9.15 9.13                                                                        13.15 13.12        17                                                                                ##STR38## CH.sub.2 CH.sub.2 CH.sub.2                                                                O  CH.sub.2 CH.sub.2 CH.sub.3                                                               88-91                                                                              C.sub.20 H.sub.33 N.sub.3                                                     O.sub.2 69.13 69.18                                                                      9.57 9.57                                                                        12.09 12.12        18                                                                                ##STR39## CH.sub.2 CH.sub.2 CH.sub.2                                                                O  (CH.sub.2).sub.17 CH.sub.3                                                               100-102                                                                            C.sub.34 H.sub.61 N.sub.3                                                     O.sub.2 75.09 75.19                                                                      11.13 11.33                                                                      7.73 7.75          19                                                                                ##STR40## CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                 ##STR41## 94-96                                                                              C.sub.22 H.sub.35 N.sub.3                                                     O.sub.2 70.74 70.91                                                                      9.44 9.45                                                                        11.25 11.30        20                                                                                ##STR42## CH.sub.2 CH.sub.2 CH.sub.2                                                                S                                                                                 ##STR43## 114-116                                                                            C.sub.23 H.sub.31 N.sub.3                                                     O.sub.2 S                                                                             66.80 66.60                                                                      7.56 7.60                                                                        10.16 10.05        21                                                                                ##STR44## CH.sub.2 CH.sub.2 CH.sub.2                                                                O  CH.sub.3   73-75                                                                              C.sub.17 H.sub.27 N.sub.3                                                     O.sub.2 66.85 66.81                                                                      8.91 8.82                                                                        13.76 13.69        22                                                                                ##STR45## CH.sub.2 CH.sub.2 CH.sub.2                                                                O  C(CH.sub.3).sub.3                                                                        94-95                                                                              C.sub.20 H.sub.33 N.sub.3                                                     O.sub.2 69.13 69.24                                                                      9.57 9.59                                                                        12.09 12.12        23                                                                                ##STR46## CH.sub.2 CH.sub.2 CH.sub.2                                                                S  CH.sub.2 CH.sub.2 CH.sub.3                                                               126-130                                                                            C.sub.19 H.sub.31 N.sub.3 OS                                                  Cl      59.12 59.14                                                                      8.36 8.35                                                                        10.89 10.93        24                                                                                ##STR47## CH.sub.2 CH.sub.2 CH.sub.2                                                                S                                                                                 ##STR48## 69-71                                                                              C.sub.20 H.sub.33 N.sub.3                                                             66.07 66.13                                                                      9.15 9.15                                                                        11.56 11.57        25                                                                                ##STR49## (CH.sub.2).sub.4                                                                          O                                                                                 ##STR50## 90-91                                                                              C.sub.23 H.sub.31 N.sub.3                                                     O.sub.2 Mass: 397 (M.sup.+)      26                                                                                ##STR51## (CH.sub.2 ).sub.4                                                                         O  CH.sub.2 CH.sub.2 CH.sub.3                                                                 73-74.5                                                                          C.sub.19 H.sub.31 N.sub.3                                                     O.sub.2 68.43 68.05                                                                      9.37 9.30                                                                        12.60 12.56        27                                                                                ##STR52## CH.sub.2 CH.sub.2 CH.sub.2                                                                S                                                                                 ##STR53## 107-108                                                                            C.sub.23 H.sub.31 N.sub.3                                                             66.80 66.60                                                                      7.56 7.60                                                                        10.16 10.05        28                                                                                ##STR54## CH.sub.2 CHCHCH.sub.2 trans                                                               O  CH.sub.3   91-94                                                                              C.sub.18 H.sub.27 N.sub.3                                                     O.sub.2 68.11 67.83                                                                      8.57 8.70                                                                        13.24 13.07        29                                                                                ##STR55## CH.sub.2 CHCHCH.sub.2 cis                                                                 O  CH.sub.3   65-67                                                                              C.sub.18 H.sub.27 N.sub.3                                                     O.sub.2 68.11 68.09                                                                      8.57 8.66                                                                        13.24 13.20        30                                                                                ##STR56## CH.sub.2 CHCHCH.sub.2 trans                                                               O  CH.sub. 2 CH.sub.3                                                                       66-69                                                                              C.sub.19 H.sub.29 N.sub.3                                                     O.sub.2 68.85 68.45                                                                      8.82 8.92                                                                        12.68 12.40        31                                                                                ##STR57## CH.sub.2 CHCHCH.sub.2 cis                                                                 O  CH.sub.2 CH.sub.3                                                                        72-74                                                                              C.sub.19 H.sub.29 N.sub.3                                                     O.sub.2 68.85 68.85                                                                      8.82 8.88                                                                        12.68 12.62        32                                                                                ##STR58## CH.sub.2 CHCHCH.sub.2 trans                                                               O  CH.sub.2 CH.sub.2 CH.sub.3                                                               87-89                                                                              C.sub.20 H.sub.31 N.sub.3                                                     O.sub.2 69.53 69.70                                                                      9.04 9.10                                                                        12.16 12.17        33                                                                                ##STR59## CH.sub.2 CHCHCH.sub.2 cis                                                                 O  CH.sub.2 CH.sub.2 CH.sub.3                                                               70-73                                                                              C.sub.20 H.sub.31 N.sub.3                                                     O.sub.2 Mass: 345 (M.sup.+)      34                                                                                ##STR60## CH.sub.2 CHCHCH.sub.2 trans                                                               O  C(CH.sub.3).sub.3                                                                        100-102                                                                            C.sub.21 H.sub.33 N.sub.3                                                     O.sub.2 70.16 70.23                                                                      9.25 9.15                                                                        11.69 11.70        35                                                                                ##STR61## CH.sub.2 CHCHCH.sub.2 trans                                                               O                                                                                 ##STR62## 101-103                                                                            C.sub.24 H.sub.31 N.sub.3                                                     O.sub.3 70.39 70.11                                                                      7.63 7.61                                                                        10.26 10.23        36                                                                                ##STR63## CH.sub.2 CHCHCH.sub.2 cis                                                                 O                                                                                 ##STR64## 88-90                                                                              C.sub.24 H.sub.31 N.sub.3                                                     O.sub.3 70.39 70.44                                                                      7.63 7.67                                                                        10.26 10.23        37                                                                                ##STR65## CH.sub.2 CH.sub.2 CH.sub.2                                                                O  CH.sub.3   106-108                                                                            C.sub.17 H.sub.27 N.sub.3                                                     O.sub.3 63.53 63.47                                                                      8.47  8.49                                                                       13.07 13.00        38                                                                                ##STR66## CH.sub.2 CH.sub.2 CH.sub.2                                                                O  CH.sub.3   73-76                                                                              C.sub.18 H.sub.29 N.sub.3                                                     O.sub.2 Mass: 319 (M.sup.+)      39                                                                                ##STR67## CH.sub.2 CH.sub.2 CH.sub.2                                                                O  CH(CH.sub.3).sub.2                                                                       114-117                                                                            C.sub.19 H.sub.31 N.sub.3                                                     O.sub.3 65.30 65.27                                                                      8.94 8.94                                                                        12.02 12.07        40                                                                                ##STR68## CH.sub.2 CH.sub.2 CH.sub.2                                                                O  CH(CH.sub.3).sub.2                                                                       92-95                                                                              C.sub.20 H.sub.33 N.sub.3                                                     O.sub.2 Mass: 347 (M.sup.+)      41                                                                                ##STR69## CH.sub.2 CH.sub.2 CH.sub.2                                                                O  CH.sub.2 CH.sub.2 CH.sub.3                                                               83-85                                                                              C.sub.20 H.sub.33 N.sub.3                                                     O.sub.2 Mass: 347 (M.sup.+)      42                                                                                ##STR70## CH.sub.2 CH.sub.2 CH.sub.2                                                                O  CH.sub.2 CH.sub.3                                                                        61-64                                                                              C.sub.19 H.sub.31 N.sub.3                                                     O.sub.2 Mass: 333 (M.sup.+)      43                                                                                ##STR71## CH.sub.2 CH.sub.2 CH.sub.2                                                                O  CH.sub.2 CH.sub.3                                                                        81-83                                                                              C.sub.18 H.sub.29 N.sub.3                                                     O.sub.3 Mass: 335 (M.sup.+)      44                                                                                ##STR72## CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                 ##STR73## 126-128                                                                            C.sub.23 H.sub.31 N.sub.3                                                     O.sub.4 66.81 66.79                                                                       7.56 7.58                                                                       10.16 10.10        45                                                                                ##STR74## (CH.sub.2).sub.4                                                                          O  CH.sub.2 CH.sub.3                                                                        57-58                                                                              C.sub.19 H.sub.31 N.sub.3                                                     O.sub.2 Mass: 333 (M.sup.+)      46                                                                                ##STR75## (CH.sub.2).sub.4                                                                          O  CH.sub.2 CH.sub.2 CH.sub.3                                                               87-88                                                                              C.sub.20 H.sub.33 N.sub.3                                                     O.sub.2 Mass: 347 (M.sup.+)      47                                                                                ##STR76## (CH.sub.2).sub.4                                                                          O  CH(CH.sub.3).sub.2                                                                       54-57                                                                              C.sub.20 H.sub.33 N.sub.3                                                     O.sub.2 Mass: 347 (M.sup.+)      48                                                                                ##STR77## (CH.sub.2).sub.4                                                                          O  CH.sub.3     52-53.5                                                                          C.sub.18 H.sub.29 N.sub.3                                                     O.sub.2 Mass: 319 (M.sup.+)      49                                                                                ##STR78## (CH.sub.2).sub.2                                                                          O  CH.sub.2 CH.sub.3                                                                        oily C.sub.17 H.sub.27 N.sub.3                                                     O.sub.2 Mass: 305 (M.sup.+)      50                                                                                ##STR79## (CH.sub.2).sub.2                                                                          O  CH.sub.2 CH.sub.2 CH.sub.3                                                               65-66                                                                              C.sub.18 H.sub.29 N.sub.3                                                     O.sub.2 Mass: 319                __________________________________________________________________________                                                         (M.sup.+)            

EXAMPLE 51N-(4-Ethoxyphenyl)-N'-[3-(3-piperidinomethylphenoxy)propyl]urea

(1) To the mixture of 4-phenetidine (4.6 g) and triethylamine (3.4 g) indichloromethane (46 ml) was added ethyl chlorocarbonate (3.6 g) dropwiseunder cooling on an ice-water bath and the reaction mixture was stirredat room temperature for an hour. The reaction mixture was washed withwater, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The resulting precipitate was suspended in petroleumether and collected by filtration to give ethylN-(4-ethoxyphenylcarbamate (4.0 g; yield 56.9 %), mp 90°-92 ° C.

(2) The mixture of 3-(3-piperidinomethylphenoxy)propylamine (4.7 g) andethyl N-(4-ethoxyphenyl)carbamate (4.0 g) in 3-methoxy-2-butanol (20 ml)was refluxed for 6 hours and then concentrated under reduced pressureThe resulting residue was dissolved in dichloromethane, washed withwater, diluted hydrochloric acid solution, saturated aqueous sodiumbicarbonate solution and saturated aqueous sodium chloride solutionsuccessively and dried over magnesium sulfate. After removal of thesolvent under reduced pressure, the resulting residue was purified bysilica gel flash column chromatography to give the precipitate (0.9 g;yield 11.4 %). This precipitate was recrystallized from ethanol to givethe title compound (0.5 g), mp 109°-111 ° C.

Analysis (%) for C₂₄ H₃₃ N₃ O₃, Calcd. (Found): C, 70.04 (70.18); H,8.08 (8.06); N, 10.21 (10.20).

EXAMPLE 52N-(3,4-Methylenedioxyphenyl)-N'-[3-(3-piperidinomethylphenoxy)propyl]urea

To the solution of N,N'-carbonyldiimidazole (4.0 g) in dichloromethane(60 ml) was added the solution of 3,4-methylenedioxyaniline (3.4 g) indichloromethane (20 ml) dropwise at 0°-5° C. The mixture was stirred atthe same temperature for an hour and then stirred at room temperaturefor an hour. To the mixture was further added the solution of3-(3-piperidinomethylphenoxy)propylamine (6.1 g) in dichloromethane (30ml) at 0 ° C. The reaction mixture was stirred at the same temperaturefor an hour and then stirred at room temperature for an hour. To thereaction mixture was added water (60 ml). The organic layer wasseparated and dried over anhydrous magnesium sulfate. After removal ofthe solvent under reduced pressure, the resulting residue was suspendedin ether and collected by filtration to give the crude product (6.7 g;yield 67.0 %). This product was recrystallized from ethanol to give thetitle compound (5.0 g), mp 128°-130 ° C.

Analysis (%) for C₂₃ H₂₉ N₃ O₄, Calcd. (Found): C, 67.13 (67.13); H,7.10 (7.08); N, 10.21 (10.17).

EXAMPLE 53-60

The analytical data of the compounds of Example 53-60, synthesized assame manner as the process of Example 52, are summarized in Table 2.

                                      TABLE 2                                     __________________________________________________________________________                                                  Analysis                                                                            Calcd.                    Ex.                                    Molecular                                                                            (%)   Found                     No.                                                                              R.sub.1                                                                              A           X R.sub.2   mp (°C.)                                                                    formula                                                                              C  H  N                         __________________________________________________________________________    53                                                                                ##STR80##                                                                           CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                ##STR81##                                                                              109-111                                                                            C.sub.24 H.sub.33 N.sub.3 O.sub.3                                                    70.04 70.02                                                                      8.08 8.08                                                                        10.21 10.21               54                                                                                ##STR82##                                                                           CH.sub.2 CH.sub.2 CH.sub.2                                                                O CH(CH.sub.3).sub.2                                                                      93-95                                                                              C.sub.19 H.sub.31 N.sub.3 O.sub.2                                                    68.43 68.38                                                                      9.37 9.37                                                                        12.60 12.60               55                                                                                ##STR83##                                                                           CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                ##STR84##                                                                              68-71                                                                              C.sub.20 H.sub.33 N.sub.3 O.sub.2                                             .HCl   Mass: 347 (M.sup.+)             56                                                                                ##STR85##                                                                           CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                ##STR86##                                                                              68-71                                                                              C.sub.20 H.sub.33 N.sub.3 O.sub.2                                                    Mass: 347 (M.sup.+)             57                                                                                ##STR87##                                                                           CH.sub.2 CH.sub.2 CH.sub.2                                                                O                                                                                ##STR88##                                                                              75-77                                                                              C.sub.19 H.sub.29 N.sub.3 O.sub.2                                                    Mass: 331 (M.sup.+)             58                                                                                ##STR89##                                                                           CH.sub.2 CHCHCH.sub.2 trans                                                               O CH(CH.sub.3).sub.2                                                                      84-86                                                                              C.sub.20 H.sub.31 N.sub.3 O.sub.2                                                    69.53 69.34                                                                      9.04 9.11                                                                        12.16 12.15               59                                                                                ##STR90##                                                                           CH.sub.2 CHCHCH.sub.2 trans                                                               O                                                                                ##STR91##                                                                              75-77                                                                              C.sub.20 H.sub.29 N.sub.3 O.sub.2                                                    69.94 69.82                                                                      8.51 8.63                                                                        12.33 12.19               60                                                                                ##STR92##                                                                           CH.sub.2 CHCHCH.sub.2 trans                                                               O                                                                                ##STR93##                                                                              117-119                                                                            C.sub.25 H.sub.33 N.sub.3 O.sub.3                                                    70.89 70.65                                                                      7.85 7.77                                                                        9.92 9.82                 __________________________________________________________________________

EXAMPLE 61

N-(3-Aminophenyl)-N'-[3-(3-piperidinomethylphenoxy)propyl]urea

To the mixture ofN-(3-nitrophenyl)-N'-[3-(3-piperidinomethylphenoxy)propyl]urea (4.6 g)in ethanol (46 ml) was added tin (2.6 g). To the reaction mixture wasadded concentrated hydrochloric acid (1.9 ml) at room temperature understirring, further added concentrated hydrochloric acid (18.2 ml) underheating on a water bath. The reaction mixture was refluxed for 6 hours,concentrated under reduced pressure, diluted with water (100 ml),alkalized with aqueous sodium hydroxide solution and extracted withdichloromethane (200 ml). The organic layer was washed with saturatedaqueous sodium chloride solution, dried over anhydrous magnesium sulfateand concentrated under reduced pressure to give the crude precipitate(3.8 g; yield 88.4 %). This precipitate was recrystallized two timesfrom ethanol to give the title compound (1.8 g), mp 116°-118 ° C.Analysis (%) for C₂₂ H₃₀ N₄ O₂, Calcd. (Found): C, 69.08 (68.91); H,7.91 (7.90); N, 14.65 (14.54).

EXAMPLE 62 N-Methyl-N'-[3-(3-piperidinomethylphenoxy)propyl]urea

To DMF (10 ml) was added sodium hydride (0.7 g; 60 % in oil) portionwiseunder cooling, further added the mixture of 3-piperidinophenol (3.3 g)in DMF (7 ml) dropwise and stirred at room temperature for an hour. Tothe reaction mixture was added N-(3-chloropropyl)-N'-methylurea (2.6 g)at room temperature and stirred for 3 hours at the same temperature. Thereaction mixture was poured into water and extracted withdichloromethane. The organic layer was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The resulting residuewas suspended in petroleum ether and collected by filtration to give thecrude precipitate (2.8 g, yield 52.8 %). This precipitate wasrecrystallized from ethyl acetate to give the title compound (0.5 g).

Thus obtained compound was identified with the compound described inexample 21 by comparison of analytical data.

EXAMPLE 63

The analytical data of the compound of Example 63, synthesized as samemanner as the process of Example 62, is summarized in Table 3.

                                      TABLE 3                                     __________________________________________________________________________                                                  Analysis                                                                            Calcd.                    Ex.                                    Molecular                                                                            (%)   Found                     No.                                                                              R.sub.1   A        X R.sub.2   mp (°C.)                                                                    formula                                                                              C  H  N                         __________________________________________________________________________    63                                                                                ##STR94##                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                             O                                                                                ##STR95##                                                                              142-144                                                                            C.sub.24 H.sub.33 N.sub.3 O.sub.4                                                    67.42 67.23                                                                      7.78 7.86                                                                        9.83 9.74                 __________________________________________________________________________

EXAMPLE 64 N-Ethyl-N'-[3-(3-piperidinomethylphenoxy)propyl]urea

To DMF (5 ml) was added sodium hydride (0.5 g; 60 % in oil) portionwiseunder cooling, further added the mixture of 3-piperidinophenol (2.3 g)in DMF (7 ml) dropwise and stirred at room temperature for an hour. Tothe reaction mixture was added N-(3-chloropropyl)-N'-methylurea (2.0 g)at room temperature, stirred for 3 hours at the same temperature andallowed to stand for overnight. The reaction mixture was poured intoice-water and extracted with dichloromethane. The organic layer wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure. The resulting residue was crystallized from petroleum ether,collected by filtration to give the title compound (0.6 g). The filtratewas concentrated and purified by silica gel column chromatography(eluting with acetone) to give the further title compound (0.8 g).

Thus obtained compound was identified with the compound described inexample 16 by comparison of analytical data.

The compounds of this invention are histamine H₂ -receptor antagonistswith both strong gastric antisecretory and gastric cytoprotection asshown by following experiments.

EXPERIMENT 1 Gastric antisecretion

Male Donryu rats, weighing about 200 g, were fasted for 24 hours beforethe experiment. Under urethane anesthesia (1.25 g/kg,i.p.), the abdomenwas incised and the pylorus was ligated. The gastric cannula wasimplanted in the forestomach (Acute fistula method). Gastric secretionfrom cannula was collected into test tubes every one hour and the acidoutput was titrated. Histamine (10 mg/kg) was intramuscularly givenafter the first collection of gastric juice. Drugs were intraduodenallygiven after the second collection of the gastric juice. The results areshown in Table 4.

                  TABLE 4                                                         ______________________________________                                        Example     Dose (mg/kg, i.d.)                                                                         Inhibition (%)                                       ______________________________________                                         1          12.5         70.7                                                             25           98.5                                                  8          1            49.5                                                             3            77.5                                                             6            81.3                                                 16          5            49.5                                                             10           77.2                                                 29          3            39.1                                                             5            80.8                                                 51          1            29.0                                                             6            52.7                                                             25           97.1                                                 54          2            16.1                                                             5            68.2                                                             10           78.8                                                 Cimetidine  12.5         51.9                                                             25           80.0                                                             50           100.0                                                ______________________________________                                    

EXPERIMENT 2 Histamine H₂ -receptor antagonism

Male Hartley guinea-pigs, weighing between 300 and 400 g, were used inthe experiment. The right atrium was dissected and suspended at 0.5 gtension in a 10 ml organ bath containing Krebs-Henseleit's solution,kept at 32±1° C. and bubbled with the gas mixture (95 % O₂ and 5 % CO₂).Contractions were recorded with a force-displacement transducer througha strain gange. Cumulative concentration-response curves for thepositive chronotropic effect of histamine on atrium were displaced tothe right in parallel by drugs, and the effects of test drugs werecalculated as the pA₂ values. Drugs were added into the organ bath 5minutes before histamine treatment. The results are shown in Table 5.

                  TABLE 5                                                         ______________________________________                                               Example pA.sub.2                                                       ______________________________________                                                1      6.58                                                                   8      7.38                                                                  16      7.18                                                                  29      7.45                                                                  51      6.60                                                                  54      7.56                                                                  Cimetidine                                                                            6.58                                                           ______________________________________                                    

EXPERIMENT 3 Gastric cytoprotection (0.6 N HCl-induced gastric lesions)

Male Donryu rats, weighing about 200 g, were deprived of food and waterfor 24 hours. One ml of 0.6N HCl solution was given orally and theanimals were killed an hour later. The stomach of each animal wasremoved and fixed 0.5 % neutral formalin solution according to themethod of Brodie and Hanson (Gastroenterology 38, 353-360, 1960). Thelength (mm) of each gastric lesion was measured under a dissectingmicroscope, summed, and used as an index for evaluation. Drugs wereorally given an hour before 0.6 N HCl solution treatment. The resultsare shown in Table 6.

                  TABLE 6                                                         ______________________________________                                        Example     Dose (mg/kg, p.o.)                                                                         Inhibition (%)                                       ______________________________________                                         1          25           30.1                                                             50           45.1                                                             100          67.4                                                  8           1           26.4                                                              6           55.4                                                             16           67.4                                                 16           6           52.6                                                             25           78.0                                                             50           89.4                                                 29           5           49.3                                                             25           73.8                                                 51          50           63.4                                                 54           6           36.1                                                             25           73.0                                                             50           70.1                                                 Cimetidine  100          22.0                                                 ______________________________________                                    

These data suggest that the compounds of this invention are histamine H₂-receptor antagonists with both strong gastric antisecretion and gastriccytoprotection. Furthermore, their gastric antisecretion were morepotent than that of cimetidine. That is, the compounds of this inventionmay process more potent antiulcer activity for the treatment of pepticulcer in clinical therapy.

What is claimed is:
 1. A urea compound of the formula (I): ##STR96##wherein R₁ indicates a piperidino group or pyrrolidino group which maybe substituted with a hydroxy group or a lower alkyl group having 1 to 3carbon atoms; A indicates an ethylene, propylene, butylene or butenylenegroup; R₂ indicates a cycloalkyl group having 3 to 6 carbon atoms, abenzyl group, or a phenyl group which may have 1 to 3 substitutentsselected from the group consisting of lower alkyl having 1 to 3 carbonatoms, lower alkoxy having 1 to 3 carbon atoms, halogen,trifluoromethyl, amino, nitro or methylenedioxy; X indicates oxygen, orthe hydrate or a pharmaceutically acceptable acid addition salt thereof.2. The compound as claimed in claim 1, wherein R₁ indicates a piperidinogroup.
 3. The compound as claimed in claim 1, wherein R₁ indicates a4-methylpiperidino group.
 4. The compound as claimed in claim 1, whereinR₁ indicates a 4-hydroxypiperidino group.
 5. The compound as claimed inclaim 1, wherein R₂ indicates a straight or branched lower alkyl grouphaving 1 to 6 carbon atoms.
 6. The compound as claimed in claim 1,wherein R₂ indicates a cycloalkyl group having 3 to 6 carbon atoms. 7.The compound as claimed in claim 1, wherein A indicates a propylene orbutenylene group.
 8. An anti-ulcer pharmaceutical composition containinga therapeutically effective amount of a compound of formula (I):##STR97## wherein R₁ indicates a piperidino group or a pyrrolidino groupwhich may be substituted with a hydroxy group or a lower alkyl grouphaving 1 to 3 carbon atoms; A indicates an ethylene, propylene, butyleneor a butyenylene group; R₂ indicates a cycloalkyl group having 3 to 6carbon atoms, a benzyl group, or a phenyl group which may have 1 to 3substituents selected from the group consisting of lower alkyl having 1to 3 carbon atoms, lower alkoxy having 1 to 3 carbon atoms, halogen,trifluoromethyl, amino, nitro or methylenedioxy; X is oxygen, thehydrate or a pharmaceutically acceptable acid addition salt thereof; andan inert pharmaceutically acceptable carrier.